Many disorders which manifest in symptoms such as respiratory distress, growth abnormalities, muscular insufficiency, and/or mental retardation result from the inheritance of genetic material which is defective in that a gene coding for the synthesis of a protein is either completely or partially absent or of an incorrect coding sequence. Thus the defect results in the disruption of the normal activities of cells which are dependent upon the normal protein for correct functioning.
The affected protein can be for example an enzyme, a storage protein, a transport protein, a hormone, a recognition protein such as a cell surface receptor or a cell pore protein.
Typical examples of disorders of this type are cystic fibrosis, Tay-Sachs disease. B-thalassaemia and Hurler disease.
If the particular genetic defect can be identified, there is the possibility that it can be correctable by providing the patient with a correct version of the gene.
Herpes simplex virus (HSV) has been considered to have potential as a vector for such gene therapy, because it has the potential to carry large inserts of foreign DNA and because it is capable of existing as a latent, quiescent genetic element in cells (particularly neurones) for the lifetime of the host. Nevertheless, a disadvantage of wild-type HSV is that it is a lytic virus whose growth results in cell damage or cell death. Therefore, the use of an unmodified form of an HSV virus vector is unacceptable, and even some modified forms can carry significant risks.
The construction and characterization of a HSV-1 mutant (in1814) unable to transinduce immediate early gene expression, and essentially avirulent when injected into mice is described by C I Ace et al. J Virol 63(5) 1989 pp 2260-2269, and specification WO 91/02788 (C M Preston & C I Ace: University of Glasgow) describes HSV1 mutants including in1814 capable of establishing latent infection in a neuronal host cell and of causing expression of an inserted therapeutic gene.
In mutants such as in1814 the gene for VP16 is modified: VP16 is a structural component of the virus particle which acts as a transcriptional activator of immediate-early genes of the infecting genome. This mutant enters cells normally. although it has a reduced ability to enter the productive lytic cycle.